【作者】 王斌；

【导师】 焉传祝；

【作者基本信息】 山东大学 ， 神经病学（专业学位）， 2023， 硕士

【摘要】 背景与目的脊髓性肌萎缩症(spinal muscular atrophy,SMA)是一种罕见的遗传性神经肌肉病,通常是由染色体5q13.2上的运动神经元存活基因1(Survival motor neuron 1,SMN1)发生纯合缺失或其他双等位基因致病性变异,导致SMN蛋白水平不足、脊髓前角α运动神经元及低位脑干运动神经元退行性变。主要表现为进行性肌无力、肌张力低下和肌肉萎缩,发病率约为1/11000,人群携带率为1/72～1/47,是最常见的婴幼儿致死性遗传性神经肌肉病。SMA的药物治疗取得了极大进展,诺西那生(Nusinersen)是一种改良的反义寡核苷酸(antisense oligonucleotides,ASO),通过增加SMN1的补救基因SMN2的完整表达以增加SMN蛋白量,从而达到治疗目的。该药已获得美国FDA批准用于SMA患者的治疗,并在2019年在我国全年龄段的SMA患者中获得批准。然而,由于价格高昂,其临床应用受到了限制,直至2022年1月,诺西那生大幅度降价并进入我国国家医保,越来越多的SMA患者接受了该药治疗。本研究的主要目的是获取我国青少年及成人SMA患者接受诺西那生治疗的真实数据,以评估其疗效和安全性,并为我国SMA患者的诊疗管理提供重要参考。对象与方法本项为双中心、前瞻性、观察性研究。纳入2022年1月至2022年10月在山东大学齐鲁医院中心院区及青岛院区神经内科接受诺西那生规范治疗的青少年及成人SMA患者,治疗随访时间至少为6个月,最长为10个月。收集纳入患者的一般临床资料、临床特点及基因检查报告,并在应用诺西那生治疗的第0、2、6和10月时对其完善Hammersmith 功能性运动扩展量表(Hammersmith Functional Motor Scale Expanded,HFMSE)、修订版上肢模块(Revised Upper Limb Module,RULM)、肌萎缩侧索硬化症功能评分量表(Amyotrophic lateral Sclerosis Functional Rating scale revised,ALSFRS-r)评估,另外对可行走的患者进行6分钟步行测试(6-Minute Walk Test,6MWT)。同时进行肺功能、复合肌肉动作电位(Compound Muscle Action Potential,CMAP)波幅、脑脊液蛋白、骨密度及身体成分的检测。将收集到的数据整理后进行统计学分析。结果:1.截至2023年2月28日,完成6个月随访评估的患者有共有29例,其中有19例患者治疗达10个月。主要临床特征:男性21例,女性8例;临床分型:2型9例(31.0%),3型18例(62.1%),4型2例(6.9%)。平均起始治疗年龄为26岁。可行走的患者有8例(27.6%),可维持站立有2名(6.9%),可保持独坐的有8例(27.6%),只能卧床的有11例(27.9%)。中重度脊柱侧弯患者15例(51.7%),舌肌纤颤的患者有11例(37.9%)。2.对比基线HFMSE中位评分13.00(3.00-36.00),治疗开始后第2个月16.00(6.00-38.50)、第6个月中位评分为22.00(9.00-33.50)和第10个月中位数为16.00(7.00-44.00),均有明显提升。治疗第2个月时29例患者中有9例(31%),6个月时29例患者中有13例(44.8%),10个月时19例患者中有7例(36.8%)的HFMSE评分有临床意义改善。3.与基线RULM中位评分22.00(9.00-33.50)对比,治疗开始后的第2个月24.00(11.50-35.00)、第 6 个月 27.00(13.50-36.00)和第 10 个月 23.00(17.00-36.00),均有明显提升。在治疗2个月时,29例患者中有11例(37.9%)的RULM评分有临床有意义的改善,治疗6月时有14例(48.3%),10个月时19例患者中有8例(42.1%)。4.根据患者的临床分型,有无行走能力,脊柱侧弯程度,有无关节挛缩,有无舌肌震颤分成了各亚组,对其治疗2月、6月、10月的运动功能评分变化进行对比,组间并未见明显差异性。5.共9名可行走的SMA患者在治疗2月和治疗6月时与基线相对比,患者6MWT的步行距离平均提升分别为33.11米和52.33米。其中有7例患者完成了治疗10月的评估,与基线对比平均提升55.94米。6.患者基线时ALSFRS-r平均评分34.3±8.5,治疗后第2个月平均评分为34.96(平均差值 0.62[95%CI[0.98-1.14]),在治疗第 6 个月时平均分为 35.24(0.89[0.28-1.50]),第10个月平均分为34.78(0.89;[0.10-1.68]),与基线水平相比均稍有提升。7.有21例患者完成用力肺活量(Forced Vital Capacity,FVC)治疗第6个月和基线的对比,结果无统计学差异。16例患者完成全身骨密度(Total Body Less Head Bone Mineral Density,TBLH BMD)检查对比,6月治疗后Z值出现了有统计学意义的下降;腰椎骨密度(Lumbar Spine Bone Mineral Density,LS BMD)、全身脂肪百分比变化、相对骨骼肌质量指数(Relative Skeletal Muscle Index,RSMI)检测,对比治疗6月与基线均无统计学差异。8.队列中13例患者完成了治疗前和治疗6个月后CMAP波幅对比,正中神经CMAP波幅平均值较基线水平增加1.33mV,腓总神经平均值较基线水平增加1.38mV;而尺神经和胫神经CMAP波幅对比治疗前后没有统计学意义的改变。9.有2例伴有严重脊柱侧弯的成人SMA2型患者在超声引导下多次腰椎穿刺均未成功,经患者及家属知情同意后成功实施腰椎蛛网膜下腔Ommaya囊植入术,建立了永久性皮下鞘内注射给药通道。10.治疗相关不良事件:11例(37.9%)患者发生不良事件,总计44次(26.8%),其中头痛15次(34.1%)、头晕11次(25.0%)和恶心11次(25.0%)最常见。结论:1.规律鞘内注射诺西那生能有效改善我国青少年和成人SMA患者的运动功能且相对安全,但治疗6-10个月对限制性通气功能患者FVC改善不明确。2.6-10个月诺西那生的治疗不能明显改善SMA患者骨密度及身体成分。3.有限的病例表明对于穿刺困难或穿刺失败的患者,实施腰椎蛛网膜下腔Ommaya囊植入术以建立永久性皮下鞘内注射给药通道是安全可行的。更多还原

【Abstract】 Background and objectiveSpinal muscular atrophy(SMA)is a rare genetic neuromuscular disease,usually caused by homozygous deletion of the survival motor neuron 1(SMN1)gene or other biallelic pathogenic variants located on chromosome 5q13.2,leading to insufficient SMN protein level and degeneration of spinal anterior horn alpha motor neurons and lower brainstem motor neurons.The main clinical manifestations include progressive muscle weakness,hypotonia and muscle atrophy,with a prevalence of about 1 in 11,000 and a carrier rate of 1/72 to 1/47,making it the most common fatal inherited neuromuscular disease in infants and young children.Significant progress has been made in the drug therapy of SMA.Nusinersen is an improved antisense oligonucleotide(ASO)that increases the complete expression of SMN2,a compensatory gene for SMN1,to increase the amount of SMN protein and achieve therapeutic effects.The drug has been approved by the US FDA for the treatment of SMA patients and was approved in 2019 for use in SMA patients of all ages in China.However,due to the high cost,its clinical application has been limited until January 2022,when nusinersen was significantly reduced in price and entered the Chinese national medical insurance,allowing more SMA patients to receive the drug treatment.The main purpose of this study is to obtain real-world data on the treatment of nusinersen in Chinese adolescent and adult SMA patients,to evaluate its efficacy and safety,and to provide important reference for the diagnosis and management of SMA in China.MethodsThis is a prospective,observational study conducted at two centers.Adolescents and adults with SMA who received standard nusinersen treatment at the neurology department of Qilu Hospital and Qingdao Hospital affiliated with Shandong University from January to October 2022 were included.The follow-up time of treatment was at least 6 months and up to 10 months.General clinical data,clinical characteristics,and genetic testing reports of the included patients were collected,and the Hammersmith Functional Motor Scale Expanded(HFMSE),Revised Upper Limb Module(RULM),and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised(ALSFRS-r)were evaluated at 0,2,6,and 10 months of nusinersen treatment.In addition,the 6-Minute Walk Test(6MWT),pulmonary function,compound muscle action potential(CMAP)amplitude,cerebrospinal fluid protein,bone density,and body composition were measured.The collected data were statistically analyzed.Results1.As of February 28,2023,a total of 29 patients completed the 6-month follow-up evaluation,and 19 patients completed the 10-month follow-up evaluation.The main clinical features:there were 21 males and 8 females with a male to female ratio of 2.6:1.Clinical classification:9 cases(31.0%)were type 2,18 cases(62.1%)were type 3,and 2 cases(6.9%)were type 4.The mean age at treatment initiation was 26 years.The median age of onset was 1.25 years.The average age of genetic diagnosis was 16.29 years,and the average time from onset to diagnosis was 11.42 years.There were 8 patients(27.6%)who could walk,2 patients(6.9%)who could maintain standing,8 patients(27.6%)who could sit independently,and 11 patients(27.9%)who were bedridden.Among them,there were 15 patients(51.7%)with moderate to severe scoliosis and 11 patients(37.9%)with tongue muscle fibrillation.2.Compared with the baseline HFMSE median score of 13.00(3.00-36.00),the median scores at the 2nd,6th,and 10th months of treatment were 16.00(6.00-38.50),22.00(9.0033.50),and 16.00(7.00-44.00),respectively,showing significant improvement.At the 2nd month of treatment,there were 9 out of 29 patients(31%)who had a clinically significant improvement(≥3-point increase)in HFMSE score,with 13 out of 29 patients(44.8%)at the 6th month,and 7 out of 19 patients(36.8%)at the 10th month.3.Compared with the baseline RULM median score of 22.00(9.00-33.50),the median scores at the 2nd,6th,and 10th months of treatment were 24.00(11.50-35.00),27.00(13.5036.00),and 23.00(17.00-36.00),respectively,showing significant improvement.At the 2nd month of treatment,there were 11 out of 29 patients(37.9%)who had a clinically significant improvement(≥2-point increase)in RULM score,with 14 out of 29 patients(48.3%)at the 6th month,and 8 out of 19 patients(42.1%)at the 10th month.4.According to the clinical classification of the patients,including walking ability,degree of spinal curvature,presence of joint contracture,and tongue tremor,they were divided into subgroups.The changes in motor function scores after 2,6,and 10 months of treatment were compared between the groups,and no significant differences were observed between the subgroups.5.Among the 9 SMA patients who could walk,their average 6MWT distance increased by 33.11 meters and 52.33 meters compared to baseline at the 2nd and 6th months of treatment,respectively.Seven of these patients completed the evaluation at the 10th month,with an average increase of 55.94 meters compared to baseline.6.The baseline ALSFRS-r score of the patients was 34.3±8.5.The average scores at the 2nd,6th,and 10th months of treatment were 34.96(mean difference 0.62[95%Cl 0.98-1.14]),35.24(0.89[0.28-1.50]),and 34.78(0.89;0.10-1.68),respectively,all slightly higher than the baseline level.7.Twenty-one patients completed a comparison of Forced Vital Capacity(FVC)at the 6th month of treatment and baseline,with no statistically significant difference.Sixteen patients completed a comparison of Total Body Less Head Bone Mineral Density(TBLH BMD),with a statistically significant decrease in Z value of 0.15 at 6 months of treatment.There was no statistically significant difference in Lumbar Spine Bone Mineral Density(LS BMD),whole-body fat percentage change,or Relative Skeletal Muscle Index(RSMI)between the 6th month of treatment and baseline.8.Thirteen patients in the cohort completed a comparison of compound muscle action potential(CMAP)amplitude before and 6 months after treatment.The average CMAP amplitude of the median nerve increased by 1,33 mV compared to baseline after 6 months of treatment,while the average CMAP amplitude of the peroneal nerve increased by 1.38 mV compared to baseline after 6 months of treatment.There was no statistically significant change in CMAP amplitude of the ulnar nerve and tibial nerve before and after treatment.9.Two adult SMA type 2 patients with severe spinal curvature failed multiple attempts of lumbar puncture under ultrasound guidance.With the informed consent of the patients and their families,a successful subarachnoid Ommaya reservoir implantation was performed,establishing a permanent subcutaneous conduit for intrathecal injection.10.Treatment-related adverse events:11(37.9%)patients experienced a total of 44 adverse events(26.8%),with the most common being headaches(15 events,34.1%),dizziness(11 events,25.0%),and nausea(11 events,25.0%).Conclusions1.Regular intrathecal injections of Nusinersen significantly improve motor function and are relatively safe for Chinese adolescent and adult SMA patients.However,the improvement in respiratory function during 6-10 months of treatment is not ideal.2.Nusinersen treatment for 6-10 months does not significantly improve bone density and body composition in SMA patients.3.For patients with difficult or failed punctures,it is recommended to undergo subarachnoid Ommaya reservoir implantation surgery to establish a permanent subcutaneous conduit for injection.更多还原